Assessing the potential for prevention or earlier detection of on-site monitoring findings from randomised controlled trials: further analyses of findings from the prospective TEMPER triggered monitoring study

Abstract

Background/Aims Clinical trials should be designed and managed to minimise important errors with potential to compromise patient safety or data integrity, employ monitoring practices that detect and correct important errors quickly, and take robust action to prevent repetition. Regulators highlight the use of risk-based monitoring, making greater use of centralised monitoring and reducing reliance on centre visits. The TEMPER study was a prospective evaluation of triggered monitoring (a risk-based monitoring method), whereby centres are prioritised for visits based on central monitoring results. Conducted in three UK-based randomised cancer treatment trials of investigational medicine products with time-to-event outcomes, it found high levels of serious findings at triggered centre visits but also at visits to matched control centres that, based on central monitoring, were not of concern. Here, we report a detailed review of the serious findings from TEMPER centre visits. We sought to identify feasible, centralised processes which might detect or prevent these findings without a centre visit. Methods We considered a representative example of each finding type through a three-staged consensus exercise. 1: Three trialists independently reviewed the issues and graded their potential for detection by central monitoring or prevention by some described process, each on a five-point scale. 2. Results of round 1 were shared anonymously and each trialist re-reviewed the list choosing whether or not to change their grading. 3. The three trialists discussed and agreed grades for any issues without consensus, and proposed a feasibility score for each proposed process. In a consultation exercise, the proposed processes were reviewed and rated for feasibility by an invited external trialist group. The primary outcome was the proportion of all major and critical findings theoretically detectable or preventable through a feasible, centralised process. Results In TEMPER, 312 major or critical findings were identified at 94 visits. These findings comprised 120 distinct issues, for which we proposed 56 different centralised processes. Following independent review of the feasibility of the proposed processes by 87 consultation respondents across different stakeholder groups, we conclude that 306/312 (98%) findings could theoretically be prevented or identified centrally. Conclusions This work presents a best-case scenario, where a large majority of monitoring findings were deemed theoretically preventable or detectable by central processes. Caveats include the cost of applying all necessary methods, and the resource implications of enhanced central monitoring for both centre and trials unit staff. Of processes not currently deemed feasible, use of electronic health records has the largest potential benefit. Our results will inform future monitoring plans and emphasise the importance of continued critical review of monitoring processes and outcomes to ensure they remain appropriate. Key words: monitoring, central monitoring, on-site monitoring, risk-based monitoring, efficient trial conduct